PMS2 monoallelic mutation carriers: the known ...

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Genet Med. Author manuscript; available in PMC 2016 July 01. Published in final edited form as: Genet Med. 2016 January ; 18(1): 13–19. doi:10.1038/gim.2015.27.

PMS2 monoallelic mutation carriers: the known unknown

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McKinsey L. Goodenberger, MS1, Brittany C. Thomas, MS1, Douglas Riegert-Johnson, MD2, C. Richard Boland, MD3, Sharon E. Plon, MD, PhD4, Mark Clendenning, PhD5, Aung Ko Win, MBBS, MPH, PhD6, Leigha Senter, MS7, Steven M. Lipkin, MD, PhD8, Zsofia K. Stadler, MD9, Finlay A. Macrae, MD10, Henry T. Lynch, MD11, Jeffrey N. Weitzel, MD12, Albert de la Chapelle, MD, PhD7, Sapna Syngal, MD, MPH13, Patrick Lynch, JD, MD14, Susan Parry, FRACP15, Mark A. Jenkins, PhD6, Steven Gallinger, FRCSC, MD, MSc16, Spring Holter, MS16, Melyssa Aronson, MS16, Polly A. Newcomb, PhD17, Terrilea Burnett, PhD18, Loïc Le Marchand, MD, PhD18, Pavel Pichurin, MD19, Heather Hampel, MS7, Jonathan P. Terdiman, MD20, Karen H. Lu, MD21, Stephen Thibodeau, PhD1, and Noralane M. Lindor, MD22 1

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Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 2 Department of Medical Genetics, Mayo Clinic, Jacksonville, Florida 3 Department of Internal Medicine, Gastroenterology, Baylor Research Institute, Charles Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas 4 Baylor College of Medicine, Houston, Texas 5 Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia 6 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia 7 Comprehensive Cancer Center, The Ohio State University, Columbus, OH 8 Genetic Epidemiology Research Institute, University of California, Irvine, Irvine, California 9 Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10 The Royal Melbourne Hospital, Victoria, Australia 11 Department of Preventive Medicine and Public Health, Creighton University, Omaha, Nebraska 12 Division of Clinical Cancer Genetics, City of Hope, Duarte, CA 13 Division of Gastroenterology, Brigham and Women's Hospital and Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA 14 Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 15 New Zealand Familial Gastrointestinal Cancer Registry, Auckland City Hospital, Auckland, New Zealand 16 Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Canada 17 Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 18 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 19 Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota 20 Division of Gastroenterology, University of California, San Francisco School of Medicine, San Francisco, California 21 Department of Gynecologic Oncology and Reproductive Medicine, M. D. Anderson Cancer Center 22 Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ

Abstract Germline mutations in MLH1, MSH2, MSH6 and PMS2 have been shown to cause Lynch syndrome. The penetrance for cancer and tumor spectrum has been repeatedly studied and multiple professional societies have proposed clinical management guidelines for affected

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individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared to the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age of onset and frequency of colonic screening. Published reports of PMS2 germline mutations were combined with unpublished cases from the authors’ research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with CRC were diagnosed under age 30 and each of these tumors presented on the left-side of the colon. As it is currently unknown what causes the early-onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the documented reduced penetrance.

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INTRODUCTION

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In the mid 1990s, through a convergence of scientific observations by yeast geneticists, cancer geneticists, and clinicians, the cause of Lynch Syndrome, formerly referred to as Hereditary non-Polyposis Colon Cancer, was found to be heterozygous DNA mismatch repair (MMR) gene germline mutations [reviewed by Boland and Lynch in [1]]. Mutations in MSH2 were reported in 1993 and mutations in MLH1 were reported in 1994[2-5]. PMS2 was cloned and found to be causative of Lynch syndrome in 1994 [6]. MSH6 was added to the list in 1997[7]. Although additional genes participate in the DNA mismatch repair process, only these 4 are well established as causes of Lynch Syndrome. Over the past two decades, information on disease penetrance and spectrum accumulated and multiple professional societies and experts have issued recommendations for the management of individuals with Lynch Syndrome, generally written to encompass carriers of mutations in any of these four genes[8-10]. (TABLE 1 and TABLE 2)

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In 1995, Hamilton et al. studied 14 families with “Turcot Syndrome” (the co-occurrence of colorectal polyposis with a primary tumor of the central nervous system)[11]. Germline APC mutations were found in ten families and three of the remaining four cases had evidence of a tumor DNA mismatch repair defect. Germline mutations were discovered in two, one in MLH1 and one in PMS2. The PMS2 mutation occurred in an 18 year old man with colonic adenomas, a glioblastoma at age 4 years, and café-au-lait spots. His sister had a history of rectal carcinoma. In a similarly affected, consanguineous family, Trimbath et al. identified homozygous PMS2 mutations in affected members[12]. In 2004, De Vos et al. noted that the heterozygous family members of a homozygous case appeared to have no cancer predisposition whatsoever raising the possibility that PMS2 predisposed to cancer only when biallelic mutations were present [13]. To underscore this possibility, De Vos et al. conducted further molecular analysis in the PMS2 Turcot family described by Hamiliton et al. and identified a second PMS2 mutation [13]. Analysis of PMS2 for mutations has turned out to be far more complex than for the other MMR genes due to the existence of multiple pseudogenes[14, 15]. As a result, clinical testing for PMS2 mutations was not available until

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relatively recently, and even now there exists some uncertainty about how many mutations may be missed or miscalled due to the presence of pseudogenes[15].

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Since 2004, despite limitations in mutation detection technologies, multiple studies have confirmed an increased risk for cancer in heterozygous carriers of PMS2 mutations, although penetrance for cancer is lower than for the other three MMR genes. Based on 55 families with presumably monoallelic PMS2 mutations, Senter et al. reported risk for colorectal cancer (CRC) as 15-20% by age 70, well less than half that of MLH1 and MSH2 mutation carriers[16]. The study, which ascertained cases based on tumors with selective loss of expression of PMS2 (predominantly colorectal but endometrial cases as well) found 6 cases (out of 99) with biallelic mutations, a proportion of biallelic mutation carriers that far exceeded that found in the other Lynch syndrome related genes. The six biallelic cases all demonstrated absence of PMS2 protein in the tumor tissue and adjacent normal tissue. In a 2008 review of all published cases with biallelic MMR mutations (now known as constitutional mismatch repair deficiency, CMMRD) more than half of the individuals (43/78) carried PMS2 mutations even though heterozygous PMS2 mutations are thought to account for only 1-15% of all individuals with Lynch Syndrome[17-21]. In Truninger et al. the isolated absence of PMS2 by IHC was found in 1.5% of >1000 consecutively collected CRC specimens from individuals undergoing surgical resection; that study showed a similar incidence of Lynch syndrome caused by mutations in PMS2 as Lynch syndrome caused by mutations in MSH2[22]. Clearly the phenotype associated with mutations in PMS2 differs in significant ways from those of MSH2, MLH1, and MSH6.

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Historical and recent guidelines for clinical management largely combine carriers of PMS2 mutations with all cases of Lynch syndrome[8] or propose delaying screening by 5 years [9]. The authors, all involved in the care of individuals with Lynch syndrome, formed an unfunded ad hoc virtual working group to collate and examine the available information on PMS2 monoallelic mutation carriers to consider this question: “Is there adequate data to inform clinical management guidelines for individuals with PMS2 mutations that may deviate from those formulated for individuals with mutations in the other three Lynch Syndrome genes?” A new penetrance analysis was not the objective as, like the previously published cases, the ascertainment of nearly all new unpublished cases identified came from high-risk clinics or registries. Having more families collected in such a strongly biased manner would be unlikely to provide a level of evidence needed to recommend changes in practice. This is a report of the outcomes of this working group.

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Published reports of PMS2 germline mutation carriers were identified by searching PubMed using the terms PMS2, monoallelic MMR, Lynch Syndrome, and Hereditary Non Polyposis Colon Cancer (HNPCC). This search yielded 4,554 publications, of which 100% of relevant reports of germline monoallelic PMS2 mutation carriers were included. Relevance for inclusion was cross-referenced by multiple authors. The references of all papers so identified were also reviewed for other eligible reports. All cases with putative monoallelic PMS2 germline mutations were abstracted. For case reports on biallelic mutation carriers, parents were presumed to be obligate monoallelic carriers and information on their health was

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included if the paper provided adequate detail (which was infrequent). A concerted effort was made to ensure that cases presented in multiple manuscripts were included only once in our series. Cases where monoallelic mutations were suspected only based on tumor studies (no germline testing) were not included. No efforts were made to contact authors of previous publications to request information not included in those papers.

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In addition to published cases, all unpublished cases of individuals with reported monoallelic PMS2 mutations known to the project's authors from their research registries or clinical practices were also collected if permitted by local institutional review boards. For all cases, both published and unpublished, the following information was collected when known: gender, last known age, specific PMS2 mutation, site of CRC, age(s) at diagnosis of CRC, other non-CRC cancer diagnoses and ages of diagnoses, microsatellite instability (MSI) status of any tumor or non-malignant tissue testing, PMS2 loss of expression by immunohistochemistry (IHC) on any tumor or non-malignant tissue, and method of ascertainment of the individual. Family history collection was not included as it was inconsistently available and often incomplete.

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Once collection of the entire list of cases and associated data were completed, the table was circulated to the working group for consideration. An on-line discussion was conducted via e-mail with the specific question being whether there was sufficient evidence to suggest that a modification of standard Lynch Syndrome cancer screening guidelines[9, 10] was indicated for carriers of monoallelic PMS2 mutations. Discussion was moderated and recorded by the lead and senior authors. At various points in the process, summaries of the viewpoints previously expressed were provided back to the work group in order to facilitate continued discussion. On-going discussion was pursued until all viewpoints were expressed and consensus on the conclusion as articulated in this manuscript was achieved. Throughout the discussion, all participants were invited to provide feedback on the collected data and all authors participated, at minimum by giving their agreement to the conclusion that was finally formed.

RESULTS Table S1, Table S2, and Table S3 show details regarding the 234 monoallelic PMS2 mutation carriers from 170 families that were included in the final dataset: 129 carriers were from previously published reports and 105 from previously unreported cases. This included 90 men, 101 women, and 43 with sex not specified.

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Most individuals had been diagnosed with CRC (n = 159, 68%) with a mean age of first CRC diagnosis of 48 years (range 22 – 80; age at diagnosis not available on 4 individuals). (TABLE S1) The percentage of 155 identifiable carriers that developed CRC at age in the 20s, 30s, 40s, 50s, and 60s or above is 8%(n=12), 20% (n=31), 31% (n=49), 22% (n=34), and 19% (n=29), respectively. Fifteen carriers had either synchronous or metachronous CRCs. Table 3 shows the distribution of CRCs by colorectal subsite. None of the CRCs diagnosed under the age of 30 years (0 out of 9) were located in the ascending colon or cecum

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compared with 57% (57 out of 100) diagnosed over the age of 30 years (p